Nanotechnology and its applications to medicine, known as nanomedicine, involve a wide use of nanomaterials to stimulate and guide the regenerative properties of cells. In particular, tissue ...regeneration can be promoted by enabling a controlled release of therapeutic agents, which can be done using nanoparticles. In this review article, the fundamentals of tissue regeneration are discussed, focusing on epithelial tissue, to demonstrate the importance of delivering therapeutic agents in an efficient, sustained and localized manner. Then, the methods for synthesizing metallic and polymeric nanoparticles are described. While polymeric nanoparticles can be loaded with an agent during synthesis, metallic nanoparticles must first be synthesized to later interact with therapeutic agents. This interaction can be fine-tuned by functionalizing metallic nanoparticles with organic molecules, which results in a more controlled attachment.This review highlights the importance of choosing the appropriate method of synthesis and functionalization, which must be designed considering both the type of tissue to regenerate and the nature of the agent to be transported.
Abstract Background Context Spinal instability is an acknowledged complication of spinal metastases; in spite of recent suggested criteria, it is not clearly defined in the literature. Purpose This ...study aimed to assess intra and interobserver agreement when using the Spine Instability Neoplastic Score (SINS) by all physicians involved in its management. Study Design Independent multicenter reliability study for the recently created SINS, undertaken with a panel of medical oncologists, neurosurgeons, radiologists, orthopedic surgeons, and radiation oncologists, was carried out. Patient Sample Ninety patients with biopsy-proven spinal metastases and magnetic resonance imaging, reviewed at the multidisciplinary tumor board of our institution, were included. Outcome Measures Intraclass correlation coefficient (ICC) was used for SINS score agreement. Fleiss kappa statistic was used to assess agreement on the location of the most affected vertebral level; agreement on the SINS category (“stable,” “potentially stable,” or “unstable”); and overall agreement with the classification established by tumor board. Methods Clinical data and imaging were provided to 83 specialists in 44 hospitals across 14 Spanish regions. No assessment criteria were pre-established. Each clinician assessed the SINS score twice, with a minimum 6-week interval. Clinicians were blinded to assessments made by other specialists and to their own previous assessment. Subgroup analyses were performed by clinicians' specialty, experience (≤7, 8–13, ≥14 years), and hospital category (four levels according to size and complexity). This study was supported by Kovacs Foundation. Results Intra and interobserver agreement on the location of the most affected levels was “almost perfect” (κ>0.94). Intra-observer agreement on the SINS score was “excellent” (ICC=0.77), whereas interobserver agreement was “moderate” (ICC=0.55). Intra-observer agreement in SINS category was “substantial” (k=0.61), whereas interobserver agreement was “moderate” (k=0.42). Overall agreement with the tumor board classification was “substantial” (κ=0.61). Results were similar across specialties, years of experience, and hospital category. Conclusions Agreement on the assessment of metastatic spine instability is moderate. The SINS can help improve communication among clinicians in oncology care.
Detection of drug-resistant tuberculosis is essential for the control of the disease but it is often hampered by the limitation of transport and storage of samples from remote locations to the ...reference laboratory. We performed a retrospective field study to evaluate the performance of four supports enabling the transport and storage of samples to be used for molecular detection of drug resistance using the GenoType MTBDRplus.
Two hundred Mycobacterium tuberculosis strains were selected and spotted on slides, FTA cards, GenoCards, and in ethanol. GenoType MTBDRplus was subsequently performed with the DNA extracted from these supports. Sensitivity and specificity were calculated and compared to the results obtained by drug susceptibility testing.
For all supports, the overall sensitivity and specificity for detection of resistance to RIF was between 95% and 100%, and for INH between 95% and 98%.
The four transport and storage supports showed a good sensitivity and specificity for the detection of resistance to RIF and INH in M. tuberculosis strains using the GenoType MTBDRplus. These supports can be maintained at room temperature and could represent an important alternative cost-effective method useful for rapid molecular detection of drug-resistant TB in low-resource settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Remdesivir (RDV) was the first antiviral drug approved by the FDA to treat severe coronavirus disease-2019 (COVID-19) patients. RDV inhibits SARS-CoV-2 replication by stalling the non structural ...protein 12 (nsp12) subunit of the RNA-dependent RNA polymerase (RdRp). No evidence of global widespread RDV-resistance mutations has been reported, however, defining genetic pathways to RDV resistance and determining emergent mutations prior and subsequent antiviral therapy in clinical settings is necessary. This study identified 57/149 (38.3%) patients who did not respond to one course (5-days) (
= 36/111, 32.4%) or prolonged (5 to 20 days) (
= 21/38, 55.3%) RDV therapy by subgenomic RNA detection. Genetic variants in the
gene were detected in 29/49 (59.2%) non responder patients by Illumina sequencing, including the
E83D mutation that emerged in an immunosuppressed patient after receiving 10 + 8 days of RDV, and the L838I detected at baseline and/or after prolonged RDV treatment in 9/49 (18.4%) non responder subjects. Although 3D protein modeling predicted no interference with RDV, the amino acid substitutions detected in the nsp12 involved changes on the electrostatic outer surface and in secondary structures that may alter antiviral response. It is important for health surveillance to study potential mutations associated with drug resistance as well as the benefit of RDV retreatment, especially in immunosuppressed patients and in those with persistent replication.
This study provides clinical and microbiologic data of an extended population of hospitalized patients for COVID-19 pneumonia who experienced treatment failure, detected by the presence of subgenomic RNA (sgRNA). The genetic variants found in the
pharmacological target of RDV bring into focus the importance of monitoring emergent mutations, one of the objectives of the World Health Organization (WHO) for health surveillance. These mutations become even more crucial as RDV keeps being prescribed and new molecules are being repurposed for the treatment of COVID-19. The present article offers new perspectives for the clinical management of non responder patients treated and retreated with RDV and emphasizes the need of further research of the benefit of combinatorial therapies and RDV retreatment, especially in immunosuppressed patients with persistent replication after therapy.
Imaging the Human Immunological Synapse Bello-Gamboa, Ana; Izquierdo, Juan Manuel; Velasco, Marta ...
Journal of visualized experiments,
12/2019
154
Journal Article
Recenzirano
Odprti dostop
The purpose of the method is to generate an immunological synapse (IS), an example of cell-to-cell conjugation formed by an antigen-presenting cell (APC) and an effector helper T lymphocyte (Th) ...cell, and to record the images corresponding to the first stages of the IS formation and the subsequent trafficking events (occurring both in the APC and in the Th cell). These events will eventually lead to polarized secretion at the IS. In this protocol, Jurkat cells challenged with Staphylococcus enterotoxin E (SEE)-pulsed Raji cells as a cell synapse model was used, because of the closeness of this experimental system to the biological reality (Th cell-APC synaptic conjugates). The approach presented here involves cell-to-cell conjugation, time-lapse acquisition, wide-field fluorescence microscopy (WFFM) followed by image processing (post-acquisition deconvolution). This improves the signal-to-noise ratio (SNR) of the images, enhances the temporal resolution, allows the synchronized acquisition of several fluorochromes in emerging synaptic conjugates and decreases fluorescence bleaching. In addition, the protocol is well matched with the end point cell fixation protocols (paraformaldehyde, acetone or methanol), which would allow further immunofluorescence staining and analyses. This protocol is also compatible with laser scanning confocal microscopy (LSCM) and other state-of-the-art microscopy techniques. As a main caveat, only those T cell-APC boundaries (called IS interfaces) that were at the right 90° angle to the focus plane along the Z-axis could be properly imaged and analyzed. Other experimental models exist that simplify imaging in the Z dimension and the following image analyses, but these approaches do not emulate the complex, irregular surface of an APC, and may promote non-physiological interactions in the IS. Thus, the experimental approach used here is suitable to reproduce and to confront some biological complexities occurring at the IS.
Tuberculosis (TB) remains one of the leading public health problems worldwide. Declared as a global emergency in 1993 by the WHO, its control is hampered by the emergence of multidrug resistance ...(MDR), defined as resistance to at least rifampicin and isoniazid, two key drugs in the treatment of the disease. More recently, severe forms of drug resistance such as extensively drug-resistant (XDR) TB have been described. After the discovery of several drugs with anti-TB activity, multidrug therapy became fundamental for control of the disease.
Major advances in molecular biology and the availability of new information generated after sequencing the genome of Mycobacterium tuberculosis increased our knowledge of the mechanisms of resistance to the main anti-TB drugs. Better knowledge of the mechanisms of drug resistance in TB and the molecular mechanisms involved will help us to improve current techniques for rapid detection and will also stimulate the exploration of new targets for drug activity and drug development. This article presents an updated review of the mechanisms and molecular basis of drug resistance in M. tuberculosis. It also comments on the several gaps in our current knowledge of the molecular mechanisms of drug resistance to the main classical and new anti-TB drugs and briefly discusses some implications of the development of drug resistance and fitness, transmission and pathogenicity of M. tuberculosis.
El coristoma pancreático, o páncreas heterotópico, es una condición rara en gastroenterología. Esta entidad consiste en el hallazgo de tejido pancreático aberrante, en alguna zona del tracto ...gastrointestinal, sin continuidad vascular o anatómica con el páncreas normal, es poco reportado y presenta sintomatología variable.Presentamos el caso de un individuo de 46 años con dolor abdominal a quien se le encontró mediante exámenes invasivos un divertículo duodenal, el cual al examen histopatológico e inmunohistoquímico mostró un coristoma pancreático.
Cystic Fibrosis (CF) is a monogenic, lethal disease caused by mutations in the cystic fibrosis transmembrane conductance (CFTR) gene. Here we report the production of CF-iPS cell lines from two ...different p.F508del homozygous female patients (Table 1). Two different primary cell types, skin fibroblasts and keratinocytes, were transfected with retroviral cocktails containing four: c-MYC, KLF4, OCT4 and SOX2 (MKOS) or three: KLF4, OCT4 and SOX2 (KOS) reprogramming factors. Two fibroblast-derived MKOS lines are described in the main text. The lines carry the p.F508del mutation, have a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.
El costo de capital se entiende como la rentabilidad esperada sobre la inversión realizada en la empresa por parte de los inversionistas (Besley, Brigham, y Gomez, 2001), este indicador se puede ver ...afectado por el cambio de estándares contables. Es por esto que el objetivo de la investigación es identificar el efecto en el costo de capital de las principales empresas colombianas listadas en el índice bursátil COLCAP, tras la adopción de las Normas Internacionales de Información Financiera (IFRS), por medio del análisis de diferentes empresas entre el 2009 y 2017, a través de los modelos Mínimos Cuadrados Generalizados Factibles (FGLS) y con Error Estándar Corregido en el Panel (PCSE), tomando información calculada bajo el estándar contable local y el internacional. Se evidencia que el implementar las IFRS, no genera un efecto significativo en el costo de capital, a diferencia de variables como el endeudamiento, el margen operacional, el ROE y el crecimiento de las empresas. Igualmente, se concluye que a nivel general la normativa contable inicial y la posterior son indiferentes para el cálculo del costo de capital, sin embargo, a nivel particular esta implementación hizo que algunas variables específicas si tuvieran efecto.
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